A Study of DKN-01 in Combination With Paclitaxel or Pembrolizumab (P102)

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Part A is a Dose-Escalation Study in Participants with Relapsed or Refractory Esophageal Cancer or Gastro-Esophageal Junction Tumors. Parts B, C, D and E are expansion cohorts of Patients with Relapsed or Refractory Esophageal Cancer, Gastro-Esophageal Junction Tumors and Gastric Adenocarcinoma.

Part F is a Dose-Escalation and Expansion Cohorts with DKN-01 + Pembrolizumab in Patients with Recurrent or Metastatic Esophageal Cancer, Gastroesophageal Junction Cancer or Gastric Adenocarcinoma with Wnt Signaling Alterations.

Patients who are unable to receive paclitaxel or pembrolizumab for any reason will be allowed to receive single agent DKN-01 as part of a monotherapy substudy.

Escalating dose of 150 milligrams (mg) up to 300 mg of DKN-01 administered on days 1 and 15 and 80 milligrams per meter squared of body surface area (mg/m2) of paclitaxel administered on days 1,8,15, and 22

Drug: DKN-01

Administered by IV infusion

Drug: Paclitaxel

Administered by IV infusion

Other Name: Taxol

Experimental: Part B: DKN-01 (Dose Confirmation)

Dose of DKN-01 determined in Part A will be administered to esophageal or gastro-esophageal junction cancer patients on Days 1 and 15 and 80 mg/m2 of paclitaxel administered on Days 1,8,15,and 22

Drug: DKN-01

Administered by IV infusion

Drug: Paclitaxel

Administered by IV infusion

Other Name: Taxol

Experimental: Part C: DKN-01 (Cohort Expansion)

Dose of DKN-01 determined in Part A will be administered to esophageal or gastro-esophageal junction adenocarcinoma patients on Days 1 and 15 and 80 mg/m2 of paclitaxel administered on Days 1,8,15,and 22

Drug: DKN-01

Administered by IV infusion

Drug: Paclitaxel

Administered by IV infusion

Other Name: Taxol

Experimental: Part D: DKN-01 (Cohort Expansion)

Dose of DKN-01 determined in Part A will be administered to esophageal squamous cell cancer patients on Days 1 and 15 and 80 mg/m2 of paclitaxel administered on Days 1,8,15,and 22

Drug: DKN-01

Administered by IV infusion

Drug: Paclitaxel

Administered by IV infusion

Other Name: Taxol

Experimental: DKN-01 Monotherapy Substudy

Dose of DKN-01 determined in Part A will be administered to esophageal or gastro-esophageal junction cancer patients on Days 1 and 15

Drug: DKN-01

Administered by IV infusion

Experimental: Part E: DKN-01 (Cohort Expansion)

Dose of DKN-01 determined in Part A will be administered to gastric adenocarcinoma with Wnt signaling alteration cancer patients on Days 1 and 15 and 80 mg/m2 of paclitaxel administered on Days 1,8,15,and 22

Drug: DKN-01

Administered by IV infusion

Drug: Paclitaxel

Administered by IV infusion

Other Name: Taxol

Experimental: Part F DKN-01 (Dose Escalation+Expansion)

Escalating dose on 150mg up to 300 mg of DKN-01 administered to patients with recurrent or metastatic esophageal cancer, gastroesophageal junction cancer or gastric adenocarcinoma with Wnt signaling alterations on days 1 and 15 and 200 mg of pembrolizumab administered on day 1 of a 21 day cycle

Number of subjects with dose limiting toxicities in Study Parts A and F which will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.03 [ Time Frame: Baseline to End of cycle 1 (Part A cycle is 28 days and Part F cycle is 21 days) ]

Number of subjects with adverse drug reactions and toxicities as evaluated by NCI CTCAE v4.03 of DKN-01 as monotherapy or in combination with paclitaxel or pembrolizumab [ Time Frame: Baseline until 30 days after last dose of study drug as assessed at a minimum of every 2 weeks ]

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Participants must be refractory or intolerant to at least one prior therapy(ies) for metastatic or locally advanced disease

If prior therapy consisted of palliative chemoradiation therapy, it will be considered one line of therapy

Prior treatment with paclitaxel as part of a definitive therapy regimen is acceptable. Patients who are unable to receive paclitaxel for any reason will be allowed to receive DKN-01 as a single agent.

Prior treatment anti- programmed death-1 (PD-1)/ anti-PD-ligand 1 (PD-L1) monoclonal antibody (mAb) is permitted in patients provided the patient's disease is primary refractory, and the patient is not intolerant of pembrolizumab. Patients who are not eligible to receive pembrolizumab will be allowed to receive single agent DKN-01

Tumor tissue for mandatory evaluation

Must have one or more tumors measurable on radiographic imaging as defined by the Response Evaluation Criteria in Solid Tumors (RECIST). Patients with evaluable but not measurable disease per RECIST criteria may be enrolled with the approval of the medical monitor.

Must be ≥18 years of age

Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale. A performance status of 2 on the ECOG scale may be entered upon the review and approval of the medical monitor

Disease-free of active second/secondary or prior malignancies for equal to or over 2 years with the exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in-situ" of the cervix or breast

Acceptable liver, renal, hematologic and coagulation function

For men and women of child-producing potential, the use of effective contraceptive methods during the study and for 6 months following the last dose of study drug

History of osteonecrosis of the hip or have evidence of structural bone abnormalities in the proximal femur on MRI scan that are symptomatic and clinically significant.

Systemic central nervous system (CNS) malignancy or metastasis.

Clinically significant peripheral neuropathy at the time of study entry. Patients with pre-existing peripheral neuropathy will be allowed to receive single agent DKN-01

Known osteoblastic bony metastasis

History of known or suspected autoimmune disease with the specific exceptions of vitiligo, atopic dermatitis, or psoriasis not requiring systemic treatment.

Clinically-significant gastrointestinal disorders, such as perforation, gastrointestinal bleeding, or diverticulitis.

Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

Treatment with surgery or chemotherapy within 21 days prior to study entry (42 days for nitrosoureas or mitomycin C)

Treatment with low dose chemotherapy concurrent with radiation within 14 days prior to study entry

Treatment with radiation therapy within 14 days prior to study entry

Treatment with any other investigational agent within 30 days prior to study entry

Previously treated with an anti-DKK-1 therapy

Participants who have a history of hypersensitivity reactions to TAXOL® or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil). Patients who exhibit these hypersensitivities will be eligible to receive single agent DKN-01.

Significant allergy to a pharmaceutical therapy that, in the opinion of the investigator, poses an increased risk to the participant

Treatment with corticosteroids (≥ 10 mg per day prednisone or equivalent) or other immune suppressive drugs within the 14 days prior to study entry

Active substance abuse

Receipt of any live vaccines within 30 days before the first dose of study treatment and while participating in the study

History of (non-infectious) pneumonitis that required steroids or current pneumonitis

History of interstitial lung disease

Intolerance or severe hypersensitivity (≥Grade 3) to pembrolizumab and/or of its excipients